Compositions and methods for inhibiting expression of klf-1 and bcl11a genes

Abstract

The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the KLF1 gene and the BCL11A gene, and methods of using such dsRNA compositions to inhibit expression of KLF1 and BCL11 A, respectively.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is the U.S. National Phase Application under 35 U.S.C. §371 of International Application No. PCT / US 2011 / 064275, filed Dec. 9, 2011, which claims the benefit of priority to U.S. Provisional Application Ser. No. 61 / 422,049, filed on Dec. 10, 2010, the contents of which are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]The invention relates to the specific inhibition of the expression of the KLF1 and BCL11A genes.BACKGROUND OF THE INVENTION[0003]Normal adult hemoglobin comprises four globin proteins, two of which are alpha (α) proteins and two of which are beta (β) proteins. During mammalian fetal development, particularly in humans, the fetus produces fetal hemoglobin, which comprises two γ-globin proteins, instead of the two β-globin proteins. During fetal development or infancy, depending on the particular species and individual, a globin switch occurs, referred to as the “fetal switch”, ...

AI Technical Summary

Benefits of technology

[0007]The present invention describes methods and iRNA compositions for modulating the expression of a KLF1 gene and / or a BCL11A gene. In certain embodiments, expression of KLF1 is reduced or inhibited using a KLF-specific iRNA, thereby leading to a decreased expression of adult β-globin genes. Reduced expression of KLF1 gene can also negatively regulate expression of BCL11A, thus leading to higher levels of γ (fetal) globin relative to β-globin levels. Alternatively, or in combination with inhibition of KLF1 gene expression, expression of BCL11A can be reduced or inhibited using a BCL11A-specific iRNA, thereby causing higher levels of γ (fetal) globin relative to β-globin levels. Thus, inhibition of KLF1 and / or a BCL11A gene expression using an iRNA composition featured in the invention can be a useful approach to therapies aimed at reducing the expression of adult β-globin genes, and / or increasing fetal hemoglobin (HbF) production. Such inhibition can be useful in treating hemoglobinopathies, such as β-hemoglobinopathies, sickle cell disease and the β-thalassemias.

[0029]In one embodiment, the dsRNA introduced reduces or inhibits expression of a KLF1 or BCL11A gene, or a combination thereof, in the cell.

[0032]In other embodiments, a combination of the dsRNA is introduced, wherein at least two of the dsRNA are substantially complementary to at least a part of an mRNA encoding KLF1 and BCL11A, thereby reducing or inhibiting the expression of each of a KLF1 gene and a BCL11A gene by at least 10%, 20%, 30%, 40%, 50% or more compared to a reference value, e.g., an untreated cell.

[0035]In another aspect, the invention provides methods for increasing fetal hemoglobin levels in a cell (e.g., a hematopoietic (e.g., an erythroid) cell). The method includes contacting the cell with an effective amount of one or more of the iRNAs targeting KLF1 and / or BCL11A, e.g., one or more of the iRNAs disclosed herein, thereby increasing the expression of fetal hemoglobin in the cell, or its progeny, relative to the cell prior to contacting. In one embodiment, the increase in fetal hemoglobin levels is effected by one or more of delaying a fetal switch from fetal hemoglobin to adult hemoglobin, or by reactivating fetal hemoglobin (HbF) in the adult stage. Such methods can be used to treat (e.g., ameliorate the clinical severity) of β-hemoglobin disorders, such as sickle cell anemia and β-thalassemias.

Problems solved by technology

These also include genetic defects that result in the production of abnormal hemoglobins with a concomitant impaired ability to maintain oxygen concentration.

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